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Bisphosphonate formulationRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Tablets, Lozenges, Or PillsBisphosphonate formulation description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070065507, Bisphosphonate formulation. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to formulations comprising bisphosphonates and their use in treatment of various conditions, especially such formulations for treatment of osteoporosis. BACKGROUND TO THE INVENTION [0002] Osteoporosis is a disease of bone in which the amount of bone is decreased and the strength of trabecular bone is reduced, cortical bone becomes thin and bones are susceptible to fracture. [0003] It is estimated that 10 million Americans have established osteoporosis and another 34 million have osteopenia, or low bone mass, which leads to osteoporosis. The disease is responsible for 1.5 millions fractures annually, mostly involving the lumbar vertebrae, hip, and wrist. [0004] Patients who are at risk for osteoporosis can be treated with vitamin D and calcium supplements. Bisphosphonates are also commonly used in the prophylaxis and treatment of osteoporosis and corticosteroid-induced osteoporosis. Bisphosphonates are synthetic analogues of natural pyrophosphate that inhibit osteoclast activity and decrease bone turnover and resorption. [0005] The bisphosphonates alendronic acid and risedronate sodium are considered the drugs of choice for treatment of osteoporosis, but disodium etidronate may also be used. Treatment results in lower fracture rates and higher bone density in both male and female patients. Lifestyle changes are also generally prescribed for sufferers. [0006] Whilst it is known to treat osteoporosis with bisphosphonates, there are a number of gastrointestinal symptoms associated with this class of drugs such as abdominal pain, dyspepsia, diarrhoea or constipation. Severe gastrointestinal reactions and oesophageal reactions such as oesophagitis, erosions, and ulceration have occurred. As a consequence biphosphonates should not be administered to patients with abnormalities of the oesophagus or other factors that might delay oesophageal emptying, or those unable to stand, or sit upright for at least 30 minutes (Martindale). Strict instructions are set out for taking these drugs, patients taking alendronate are instructed to take it on an empty stomach before food and to remain sitting upright without eating for at least 30 minutes after taking the drug. Similar instructions, in some case stricter, apply for other bisphosphonates. [0007] The reason for these instructions is that alendronate and other bisphosphonates can provoke severe oesophageal irritation. This can lead to reflux into the oesophagus and consequent ulceration, oesophagitis, heartburn and retrosternal pain, pain on swallowing and dysphagia. In addition to these side-effects, there is reduced patient compliance with the bisphosphonate treatment, leading to progression of the osteoporosis. [0008] Bisphosphonate treatment is so effective that it is very widely used. Patients have hitherto had to put up with the adverse symptoms associated with bisphosphonate use as there is no alternative treatment that gives such good results. [0009] WO 93/09785 and US 2003/0158154 disclose bisphosphonate formulations that contain very small amounts of surfactant, including in some instances simethicone, to facilitate tablet manufacture and give tablets a glossy appearance. [0010] An object of the invention is to ameliorate the above problems and disadvantages. An object of a specific embodiment of the invention is to provide a formulation of a bisphosphonate which provokes reduced gastric irritation and/or reduced reflux of stomach acid, leading preferably to increased patient compliance. SUMMARY OF THE INVENTION [0011] Accordingly the present invention provides a pharmaceutical formulation comprising a bisphosphonate and an antifoaming agent, and also provides for administration of a bisphosphonate in combination with an antifoaming agent. [0012] In use, for example in treatment of osteoporosis, enough antifoaming agent is present for the combination to be expected to limit the formation of foams in the stomach. Without wishing to be bound by any particular theory, it is believed that the associated concomitant decrease in the volume of stomach contents, and additionally barrier properties of some preferred antifoaming agents, will reduce the likelihood of stomach acid reflux and therefore oesophageal irritation. Hence, typical formulations of the invention comprise an amount of an antifoaming agent effective to reduce the formation of foam in the stomach. [0013] The antifoaming agent may comprise an agent to lower surface tension and/or to reduce the foaming tendency of stomach contents, and more than one agent may be advantageously used in concert to reduce foaming, and, in preferred embodiments also provide barrier protection. [0014] Formulations of the present invention may comprise an amount of an antifoaming agent in the range of 20 mg to 150 mg, preferably from 35 mg to 125 mg and specific embodiments set out in examples below have antifoaming agent present in the range of 50 mg to 100 mg--according to the United States Pharmacopeia, the minimum quantity of simethicone effective for reducing foam formation in the stomach is 20 mg. The invention also provides formulations that comprise at least 1%, preferably at least 2% antifoaming agent, and more generally an amount of an antifoaming agent in the range of 3% to 40% by weight, and preferably in the range of 5% to 30% by weight. Specific embodiments set out in the examples contain from about 7% to about 18% antifoaming agent by weight. [0015] Antifoaming agents are known to those of skill in the art. Whilst many different agents may be used in the formulations of the invention, presently there are only a limited number of approved antifoaming agents available for pharmaceutical formulations, and these are particularly suitable. Siloxanes can be used. Some embodiments use one or more polydimethylsiloxanes as the antifoaming agent. Preferred embodiments of the formulation of the invention comprise dimethicone BP, simethicone BP (an activated form of dimethicone), or both. [0016] Any bisphosphonate having the side-effect of promoting gastric irritation may suitably be used in the formulations of the invention. The invention applies generally to formulations of bisphosphonates, including for example alendronic acid, disodium etidronate, disodium pamidronate, ibandronic acid, risedronate sodium, sodium clodronate, strontium ranelate, tiludronic acid and zoledronic acid. In preferred embodiments the bisphosphonate may be selected from the group consisting of alendronic acid or alendronate, risedronate and etidronate. Particularly preferred formulations comprise alendronic acid or alendronate. Typically the amount of bisphosphonate is from 5 mg to 150 mg of Alendronic acid (or a therapeutically equivalent amount of another bisphosphonate, or an equivalent amount of a bisphosphonate compound), preferably from about 10 mg to about 70 mg. Formulations of the invention comprise also a pharmaceutically acceptable carrier. [0017] Bisphosphonates can be co-administered with other agents helpful in treatment of osteoporosis, either directly or dealing e.g. with side effects of the treatment. Formulations of the invention may thus also include one or more of a vitamin D derivative and a calcium supplement. [0018] The term `Vitamin D derivative` is used for a range of compounds which have the ability to prevent or treat rickets. Vitamin D supplements suitable for inclusion in formulations of the invention include ergocalciferol (calciferol, vitamin D2), cholecalciferol (vitamin D3), dihydrotachysterol, alfacalcidol (1.alpha.-hydroxycholecalciferol), and calcitriol (1,25-dihydroxycholecalciferol). [0019] Some calcium supplements which may be used in the formulations of the invention are calcium salts, optionally selected from calcium gluconate, calcium chloride, calcium lactate, ADCAL.RTM., CACIT.RTM., CALCICHEW.RTM., CALCIUM-500.RTM., CALCIUM-SANDOZ.RTM. and SANDOCAL.RTM.. Treatments of the invention may also be carried out in combination with parenteral calcium supplements. [0020] Particularly preferred formulations of the invention comprise a bisphosphonate, antifoaming agent, a vitamin D derivative and a calcium supplement. [0021] Formulations of the invention include an amount of one or more agents effective for reducing the tendency of the stomach contents to foam, and which may also elicit barrier protection. Treatment according to the invention involves the administration of one or more such agents with bisphosphonates simultaneously, either together (in the same formulation) or separately (taken together at the same time), or separately (time delayed administration). Continue reading about Bisphosphonate formulation... Full patent description for Bisphosphonate formulation Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Bisphosphonate formulation patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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